NEP010, a novel compound with minor structural modification from afatinib, exhibited significantly improved antitumor activity

Non-small cell lung cancer (NSCLC) is classified into many subclasses according to the specific kinase mutations. The most common mutation is epidermal growth factor receptor (EGFR) somatic mutation, which has promoted the development of several novel drugs (Tyrosine kinase inhibitors, TKIs). Although various TKIs are recom-mended as targeted therapy for NSCLC with EGFR mutations in NCCN guidelines, not all patients respond equally to the recommended TKIs, which lead to series of novel compound under development to satisfy actual clinical needs. Based on the structure of afatinib, a marketed drug recommended as the first-line therapy for patients with EGFR mutation, NEP010 was synthesized with structural modification. The antitumor efficacy of NEP010 on mouse tumor xenograft models with different EGFR mutations was determined. Results showed that with minor structural modifications on afatinib, the inhibitory effect of NEP010 on EGFR mutant tumors was significantly improved. Pharmacokinetics test was adopted, and compared with afatinib, the increased tissue exposure of NEP010 may be the potential factor responsible for the increased efficacy. Furthermore, tissue distribution test showed a high concentration of NEP010 in the lung which happens to be the target organ of NEP010 in clinical practice. In conclusion, data obtained suggested that NEP010 has an increased anti-tumor effect via improving pharmacokinetics, and may provide a potent therapeutic option for the patients with EGFR mutation of NSCLC in the future.

Automated summary

Non-small cell lung cancer (NSCLC) has various subclasses based on specific kinase mutations, with the most common being epidermal growth factor receptor (EGFR) somatic mutation. The development of tyrosine kinase inhibitors (TKIs) has been promoted for targeted therapy in NSCLC with EGFR mutations. However, not all patients respond equally to recommended TKIs, leading to the development of novel compounds. NEP010, a modified version of the marketed drug afatinib, showed improved inhibitory effects on EGFR mutant tumors. Pharmacokinetic and tissue distribution tests indicated that NEP010 may have increased efficacy by improving tissue exposure and targeting the lung, the organ of interest in clinical practice. In conclusion, NEP010 could be a potential therapeutic option for NSCLC patients with EGFR mutation.